The most crucial role of the immune system is to provide effective defence of the host against infection with pathogenic micro-organisms. To do so, two types of responses have evolved, known as innate and adaptive immunity. The overall goal of this project is to unify these two aspects of host defend by testing the hypothesis that innate immunity is triggered when receptors that have evolved over long periods of time recognize invariant microbial structures. These recognition events are proposed to be critical in inducing co-stimulatory molecules on antigen presenting cells, so that they can in turn activate T cells to mediate adaptive immune responses. Thus, the project has two broad aims. The first is to characterize cellular responses to microbial constituents, to identify receptors that mediate such responses, and to identify and characterize the receptor:ligand pairs that contribute to these innate immune reactions. To do so, monoclonal antibodies that trigger responses indistinguishable from those induced by microbial substances will be prepared and used to characterize receptors. The second broad aim is to identify molecules induced on antigen presenting cells by recognition of microbial constituents or other activators of antigen presenting cell function. This will again involve generation of monoclonal antibodies that prevent the activation of naive T cells, the characterization of their ligands, and the identification of the genes encoding these structures. Ultimately, we hope to bring these two lines of research together by showing that the innate recognition responses are crucial to adaptive immunity. This will be accomplished first by antibody blockade, and, for molecules shown in this way to be important in innate or adaptive immunity, by identifying genes critical for the induction of co- stimulatory activity and then inactivating them by homologous recombination in embryonal stem cells. The resultant mice will be tested for their ability to mount model immune responses and their capacity for resisting infection with model pathogens.